tbuckley/cabot-search huggingface dataset:
P115: Distinct signaling pathways and checkpoint molecule expression across histological subtypes of nodular lymphocyte-predominant Hodgkin lymphoma
Authors: Ilja Kalashnikov, Rachel Kositsky, Marja-Liisa Karjalainen-Lindsberg, Johannes Dunkel, Annika Pasanen, Cassandra Love, Clay Parker, Sarah Ondrejka, Eric Hsi, Ridas Juskevicius, Andrew Evans, Andrew G. Evans, Magdalena Czader, Lin Wang, Mina Xu, Nathan Paulson, Mette ølgod Pedersen, Anne Ortved Gang, Jean Koff, Chad Mccal, Yaso Natkunam, Abner Louissaint, Ong Shin Yeu, Raju Pillai, Jennifer Chapman, Catalina Amador, Amy Chadburn, Rashmi Goswami, Amir Behdad, Payal Sojitra, Eric Tse, Naresh Kikkeri, Kikkeri N. Nasresh, Yuri Fedoriw, Sandeep Dave, Sirpa Leppä
Journal: HemaSphere (2022)

Background: Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare B-cell malignancy characterized by infrequent neoplastic cells embedded in an immunologically active tumor microenvironment (TME). The composition of the TME is known to influence the outcomes; cases with a nodular B-cell rich TME (classical histology; Fan A-B) are generally indolent, whereas increased infiltration of T-cells or diffuse growth (variant histology; Fan C-F) is associated with a more aggressive clinical course. The molecular features underlying this association remain to be discovered. To gain further insights into disease biology, we recruited NLPHL cases as part of the Atlas of Blood Cancer Genomes (ABCG) initiative, a consortium consisting of 26 institutions.Design: We collected comprehensive clinicopathological data from 106 NLPHL patients, with centralized review performed by a panel of dedicated hematopathologists to ensure accurate diagnosis. We performed RNA sequencing on formalin-fixed paraffin-embedded (FFPE) diagnostic tumor samples (n=81) and enumerated tumor-infiltrating immune cell compositions using FARDEEP with signature matrix LM22 from CIBERSORT. Results: Patient demographics are shown in Table 1. Classical histology was associated with better survival compared to variant histology (Figure 1A-B). According to in silico immunophenotyping, NLPHLs with variant histology were characterized by a lower proportion of naï B cells and increased proportions of CD8+ T cells and M1-macrophages compared to the classical histology (Figure 1C). Moreover, variant histology was associated with higher expression of checkpoint genes compared to classical histology (Figure 1D; P=0.019). Higher proportions of T cells and macrophages and increased expression of checkpoint genes were particularly prominent in cases with splenic involvement. Finally, we found a strong association between variant histology and gene expression related to inflammatory response (P<0.001), whereas genes related to cell cycle regulation through the E2F pathway were upregulated in NLPHLs with classical histology (P<0.001). Conclusion: Our study represents the largest comprehensive clinical and transcriptomic analyses of NLPHL to-date. Our results indicate that TME is clinically meaningful and provide evidence for distinct signaling pathways and expression patterns of checkpoint genes across histological subtypes.
Five-Year Survival Outcomes With Nivolumab Plus Ipilimumab Versus Chemotherapy as First-Line Treatment for Metastatic Non–Small-Cell Lung Cancer in CheckMate 227
Authors: Julie R. Brahmer, Jong-Seok Lee, Tudor-Eliade Ciuleanu, Reyes Bernabe Caro, Makoto Nishio, Laszlo Urban, Clarisse Audigier-Valette, Lorena Lupinacci, Randeep Sangha, Adam Pluzanski, Jacobus Burgers, Mauricio Mahave, Samreen Ahmed, Adam J. Schoenfeld, Luis G. Paz-Ares, Martin Reck, Hossein Borghaei, Kenneth J. O'Byrne, Ravi G. Gupta, Judith Bushong, Li Li, Steven I. Blum, Laura J. Eccles, Suresh S. Ramalingam
Journal: Journal of Clinical Oncology (2022)

We present 5-year results from CheckMate 227 Part 1, in which nivolumab plus ipilimumab improved overall survival (OS) versus chemotherapy in patients with metastatic non-small-cell lung cancer, regardless of tumor programmed death ligand 1 (PD-L1) status.Adults with stage IV/recurrent non-small-cell lung cancer without EGFR mutations or ALK alterations and with tumor PD-L1 ≥ 1% or < 1% (n = 1739) were randomly assigned. Patients with tumor PD-L1 ≥ 1% were randomly assigned to first-line nivolumab plus ipilimumab, nivolumab alone, or chemotherapy. Patients with tumor PD-L1 < 1% were randomly assigned to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy. End points included exploratory 5-year results for efficacy, safety, and quality of life.At a minimum follow-up of 61.3 months, 5-year OS rates were 24% versus 14% for nivolumab plus ipilimumab versus chemotherapy (PD-L1 ≥ 1%) and 19% versus 7% (PD-L1 < 1%). The median duration of response was 24.5 versus 6.7 months (PD-L1 ≥ 1%) and 19.4 versus 4.8 months (PD-L1 < 1%). Among patients surviving 5 years, 66% (PD-L1 ≥ 1%) and 64% (PD-L1 < 1%) were off nivolumab plus ipilimumab without initiating subsequent systemic anticancer treatment by the 5-year time point. Survival benefit continued after nivolumab plus ipilimumab discontinuation because of treatment-related adverse events, with a 5-year OS rate of 39% (combined PD-L1 ≥ 1% and < 1% populations). Quality of life in 5-year survivors treated with nivolumab plus ipilimumab was similar to that in the general US population through the 5-year follow-up. No new safety signals were observed.With all patients off immunotherapy treatment for ≥ 3 years, nivolumab plus ipilimumab increased 5-year survivorship versus chemotherapy, including long-term, durable clinical benefit regardless of tumor PD-L1 expression. These data support nivolumab plus ipilimumab as an effective first-line treatment for patients with metastatic non-small-cell lung cancer.
Neonatal Monkeypox Virus Infection
Authors: Padmanabhan Ramnarayan, Rebecca Mitting, Elizabeth Whittaker, Maria Marcolin, Ciara O'Regan, Ruchi Sinha, Aisleen Bennett, Moustafa Moustafa, Neil Tickner, Mark Gilchrist, Anthony Kershaw, Tommy Rampling
Journal: New England Journal of Medicine (2022)
Migraine — Treatment and Preventive Therapies
Authors: Cynthia E. Armand, Elizabeth Loder, Allan H. Ropper
Journal: New England Journal of Medicine (2022)

In this instructional video, Drs. Cynthia Armand and Elizabeth Loder discuss the clinical presentation and pathophysiology of migraine and treatment options for patients. This video provides essential and useful information for any clinician caring for patients with this common condition. Newer acute and preventive therapies — including triptans, gepants, ditans, and injectable monoclonal antibodies — are discussed, as are the importance of a patient-centered approach and the need to tackle challenges of access to these newer agents.
Congenital Hypermetabolism and Uncoupled Oxidative Phosphorylation
Authors: Rebecca D. Ganetzky, Andrew L. Markhard, Irene Yee, Sheila Clever, Alan Cahill, Hardik Shah, Zenon Grabarek, Tsz-Leung To, Vamsi K. Mootha
Journal: New England Journal of Medicine (2022)

We describe the case of identical twin boys who presented with low body weight despite excessive caloric intake. An evaluation of their fibroblasts showed elevated oxygen consumption and decreased mitochondrial membrane potential. Exome analysis revealed a de novo heterozygous variant in ATP5F1B, which encodes the β subunit of mitochondrial ATP synthase (also called complex V). In yeast, mutations affecting the same region loosen coupling between the proton motive force and ATP synthesis, resulting in high rates of mitochondrial respiration. Expression of the mutant allele in human cell lines recapitulates this phenotype. These data support an autosomal dominant mitochondrial uncoupling syndrome with hypermetabolism. (Funded by the National Institutes of Health.).
Genome-edited allogeneic donor “universal” chimeric antigen receptor T cells
Authors: Waseem Qasim
Journal: Blood (2022)

αβ T cell receptor (TCRαβ) T cells modified to express chimeric antigen receptors (CAR), are now available as authorized therapies for certain B-cell malignancies. However the process of autologous harvest and generation of patient-specific products is costly, with complex logistics and infrastructure requirements. Premanufactured banks of allogeneic donor-derived CAR T cells could help widen applicability if the challenges of HLA-mismatched T-cell therapy can be addressed. Genome editing is being applied to overcome allogeneic barriers, most notably, by disrupting TCRαβ to prevent graft-versus-host disease, and multiple competing editing technologies, including CRISPR/Cas9 and base editing, have reached clinical phase testing. Improvements in accuracy and efficiency have unlocked applications for a wider range of blood malignancies, with multiplexed editing incorporated to target HLA molecules, shared antigens and checkpoint pathways. Clinical trials will help establish safety profiles and determine the durability of responses as well as the role of consolidation with allogeneic transplantation.
Immune Imprinting and Protection against Repeat Reinfection with SARS-CoV-2
Authors: Hiam Chemaitelly, Houssein H Ayoub, Patrick Tang, Mohammad R Hasan, Peter Coyle, Hadi M Yassine, Hebah A Al-Khatib, Maria K Smatti, Zaina Al-Kanaani, Einas Al-Kuwari, Andrew Jeremijenko, Anvar H Kaleeckal, Ali N Latif, Riyazuddin M Shaik, Hanan F Abdul-Rahim, Gheyath K Nasrallah, Mohamed G Al-Kuwari, Adeel A Butt, Hamad E Al-Romaihi, Mohamed H Al-Thani, Abdullatif Al-Khal, Roberto Bertollini, Laith J Abu-Raddad
Journal: New England Journal of Medicine (2022)
Trial of Thrombectomy 6 to 24 Hours after Stroke Due to Basilar-Artery Occlusion
Authors: Tudor G. Jovin, Chuanhui Li, Longfei Wu, Chuanjie Wu, Jian Chen, Changchun Jiang, Zhonghua Shi, Zongen Gao, Cunfeng Song, Wenhuo Chen, Ya Peng, Chen Yao, Ming Wei, Tong Li, Liping Wei, Guodong Xiao, Hua Yang, Ming Ren, Jiangang Duan, Xinfeng Liu, Qingwu Yang, Yuxiu Liu, Qingfeng Zhu, Wanchao Shi, Qiyi Zhu, Xiaobo Li, Zaiyu Guo, Qi Yang, Chengbei Hou, Wenbo Zhao, Qingfeng Ma, Yunzhou Zhang, Liqun Jiao, Hongqi Zhang, David S. Liebeskind, Hui Liang, Ashutosh P. Jadhav, Changming Wen, Scott Brown, Liangfu Zhu, Huawei Ye, Marc Ribo, Mingze Chang, Haiqing Song, Jun Chen, Xunming Ji
Journal: New England Journal of Medicine (2022)

The effects and risks of endovascular thrombectomy 6 to 24 hours after stroke onset due to basilar-artery occlusion have not been extensively studied.
Minimally invasive, sustained-release relaxin-2 microparticles reverse arthrofibrosis
Authors: Jack R. Kirsch, Amanda K. Williamson, Diana Yeritsyan, William A. Blessing, Kaveh Momenzadeh, Todd R. Leach, Patrick M. Williamson, Jenny T. Korunes-Miller, Joseph P. DeAngelis, David Zurakowski, Rosalynn M. Nazarian, Edward K. Rodriguez, Ara Nazarian, Mark W. Grinstaff
Journal: Science Translational Medicine (2022)

Substantial advances in biotherapeutics are distinctly lacking for musculoskeletal diseases. Musculoskeletal diseases are biomechanically complex and localized, highlighting the need for novel therapies capable of addressing these issues. All frontline treatment options for arthrofibrosis, a debilitating musculoskeletal disease, fail to treat the disease etiology—the accumulation of fibrotic tissue within the joint space. For millions of patients each year, the lack of modern and effective treatment options necessitates surgery in an attempt to regain joint range of motion (ROM) and escape prolonged pain. Human relaxin-2 (RLX), an endogenous peptide hormone with antifibrotic and antifibrogenic activity, is a promising biotherapeutic candidate for musculoskeletal fibrosis. However, RLX has previously faltered through multiple clinical programs because of pharmacokinetic barriers. Here, we describe the design and in vitro characterization of a tailored drug delivery system for the sustained release of RLX. Drug-loaded, polymeric microparticles released RLX over a multiweek time frame without altering peptide structure or bioactivity. In vivo, intraarticular administration of microparticles in rats resulted in prolonged, localized concentrations of RLX with reduced systemic drug exposure. Furthermore, a single injection of RLX-loaded microparticles restored joint ROM and architecture in an atraumatic rat model of arthrofibrosis with clinically derived end points. Finally, confirmation of RLX receptor expression, RXFP1, in multiple human tissues relevant to arthrofibrosis suggests the clinical translational potential of RLX when administered in a sustained and targeted manner.
Monkeypox: Virus DNA is widespread in treatment rooms, study finds
Authors: Luke Taylor
Journal: BMJ (2022)

Monkeypox: Virus DNA is widespread in treatment rooms, study finds Luke TaylorHealthcare workers treating patients with monkeypox should use personal protective equipment (PPE), regularly disinfect any frequently touched surfaces, and practise hand hygiene to protect themselves from becoming infected, researchers have said, after they found that viral DNA circulated widely in the air in hospital isolation treatment rooms. 1
Case 31-2022: A 72-Year-Old Man with Heartburn, Nausea, and Inability to Eat
Authors: Kyle D. Staller, Yousef R. Badran, David A. Rosman, Samuel J. Klempner, Richard Judelson
Journal: New England Journal of Medicine (2022)

A 72-year-old man with a history of gastroesophageal reflux disease was admitted with heartburn, nausea, and inability to eat. On a study of gastric emptying, 80% of the gastric contents had been retained at 4 hours. A diagnostic test was performed.
Trial of Endovascular Treatment of Acute Basilar-Artery Occlusion
Authors: Chunrong Tao, Raul G. Nogueira, Yuyou Zhu, Jun Sun, Hongxing Han, Guangxiong Yuan, Changming Wen, Peiyang Zhou, Wenhuo Chen, Guoyong Zeng, Yuwen Li, Zhengfei Ma, Chuanqing Yu, Junfeng Su, Zhiming Zhou, Zhongjun Chen, Geng Liao, Yaxuan Sun, Youquan Ren, Hui Zhang, Jie Chen, Xincan Yue, Guodong Xiao, Li Wang, Rui Liu, Wenhua Liu, Yong Liu, Li Wang, Chao Zhang, Tianlong Liu, Jianlong Song, Rui Li, Pengfei Xu, Yamei Yin, Guoping Wang, Blaise Baxter, Adnan I. Qureshi, Xinfeng Liu, Wei Hu
Journal: New England Journal of Medicine (2022)

Data from trials investigating the effects and risks of endovascular thrombectomy for the treatment of stroke due to basilar-artery occlusion are limited.
Translating musculoskeletal bioengineering into tissue regeneration therapies
Authors: Alastair Khodabukus, Tyler Guyer, Axel C. Moore, Molly M. Stevens, Robert E. Guldberg, Nenad Bursac
Journal: Science Translational Medicine (2022)

Musculoskeletal injuries and disorders are the leading cause of physical disability worldwide and a considerable socioeconomic burden. The lack of effective therapies has driven the development of novel bioengineering approaches that have recently started to gain clinical approvals. In this review, we first discuss the self-repair capacity of the musculoskeletal tissues and describe causes of musculoskeletal dysfunction. We then review the development of novel biomaterial, immunomodulatory, cellular, and gene therapies to treat musculoskeletal disorders. Last, we consider the recent regulatory changes and future areas of technological progress that can accelerate translation of these therapies to clinical practice.
Evaluation of Neurotoxicity in BALB/c Mice following Chronic Exposure to Polystyrene Microplastics
Authors: Haibo Jin, Chen Yang, Chengyue Jiang, Luxi Li, Mengge Pan, Dongmei Li, Xiaodong Han, Jie Ding
Journal: Environmental Health Perspectives (2022)

Background: The toxicity of microplastics (MPs) has attracted wide attention from researchers. Previous studies have indicated that MPs produce toxic effects on a variety of organs in aquatic organisms and mammals. However, the exact neurotoxicity of MPs in mammals is still unclear. Objectives: We aimed to confirm the neurotoxicity of chronic exposure to polystyrene MPs (PS-MPs) at environmental pollution concentrations. Methods: In the present study, mice were provided drinking water containing 100μg/L and 1,000μg/L PS-MPs with diameters of 0.5, 4, and 10μm for 180 consecutive days. After the exposure period, the mice were anesthetized to gain brain tissues. The accumulation of PS-MPs in brain tissues, integrity of the blood–brain barrier, inflammation, and spine density were detected. We evaluated learning and memory ability by the Morris water maze and novel object recognition tests. Results: We observed the accumulation of PS-MPs with various particle diameters (0.5, 4, and 10μm) in the brains of exposed mice. Meanwhile, exposed mice also exhibited disruption of the blood–brain barrier, higher level of dendritic spine density, and an inflammatory response in the hippocampus. In addition, exposed mice exhibited cognitive and memory deficits compared with control mice as determined using the Morris water maze and novel object recognition tests, respectively. There was a concentration-dependent trend, but no particle size-dependent differences were seen in the neurotoxicity of MPs. Conclusions: Collectively, our results suggested that PS-MPs exposure can lead to learning and memory dysfunctions and induce neurotoxic effects in mice, findings which have wide-ranging implications for the public regarding the potential risks of MPs. https://doi.org/10.1289/EHP10255
Favorable Outcomes in Endovascular Therapy for Basilar-Artery Occlusion
Authors: Wouter J. Schonewille
Journal: New England Journal of Medicine (2022)

Basilar-artery occlusion accounts for approximately 10% of ischemic strokes caused by intracranial large-vessel occlusion and is associated with the highest morbidity and mortality among all strokes.1,2 Patients with basilar-artery occlusion have largely been excluded from acute stroke trials. However, well before the efficacy of endovascular therapy was shown in patients with anterior-circulation large-vessel occlusion, many patients with basilar-artery occlusion were being treated by thrombectomy.3,4 Two preceding randomized trials were the bases for establishing power calculations and anticipating adverse events in trials involving patients with basilar-artery occlusion. The Basilar Artery International Cooperation Study (BASICS), the results of which have been previously . . .
Incidence of Chronic Kidney Disease among Adults with Diabetes, 2015–2020
Authors: Katherine R Tuttle, Cami R Jones, Kenn B Daratha, Alain K Koyama, Susanne B Nicholas, Radica Z Alicic, O Kenrik Duru, Joshua J Neumiller, Keith C Norris, Nilka Ríos Burrows, Meda E Pavkov
Journal: New England Journal of Medicine (2022)
Engineering human mini-bones for the standardized modeling of healthy hematopoiesis, leukemia, and solid tumor metastasis
Authors: Ani Grigoryan, Dimitra Zacharaki, Alexander Balhuizen, Christophe RM Côme, Alejandro Garcia Garcia, David Hidalgo Gil, Anne-Katrine Frank, Kristina Aaltonen, Adriana Mañas, Javanshir Esfandyari, Pontus Kjellman, Emelie Englund, Carmen Rodriguez, Wondossen Sime, Ramin Massoumi, Nasim Kalantari, Sujeethkumar Prithiviraj, Yuan Li, Steven J Dupard, Hanna Isaksson, Chris D Madsen, Bo T Porse, Daniel Bexell, Paul E Bourgine
Journal: Science Translational Medicine (2022)

The bone marrow microenvironment provides indispensable factors to sustain blood production throughout life. It is also a hotspot for the progression of hematologic disorders and the most frequent site of solid tumor metastasis. Preclinical research relies on xenograft mouse models, but these models preclude the human-specific functional interactions of stem cells with their bone marrow microenvironment. Instead, human mesenchymal cells can be exploited for the in vivo engineering of humanized niches, which confer robust engraftment of human healthy and malignant blood samples. However, mesenchymal cells are associated with major reproducibility issues in tissue formation. Here, we report the fast and standardized generation of human mini-bones by a custom-designed human mesenchymal cell line. These resulting humanized ossicles (hOss) consist of fully mature bone and bone marrow structures hosting a human mesenchymal niche with retained stem cell properties. As compared to mouse bones, we demonstrate superior engraftment of human cord blood hematopoietic cells and primary acute myeloid leukemia samples and also validate hOss as a metastatic site for breast cancer cells. We further report the engraftment of neuroblastoma patient-derived xenograft cells in a humanized model, recapitulating clinically described osteolytic lesions. Collectively, our human mini-bones constitute a powerful preclinical platform to model bone-developing tumors using patient-derived materials.
Translating diagnostics and drug delivery technologies to low-resource settings
Authors: Erin M. Euliano, Alexandros A. Sklavounos, Aaron R. Wheeler, Kevin J. McHugh
Journal: Science Translational Medicine (2022)

Diagnostics and drug delivery technologies engineered for low-resource settings aim to meet their technical design specifications using strategies that are compatible with limited equipment, infrastructure, and operator training. Despite many preclinical successes, very few of these devices have been translated to the clinic. Here, we identify factors that contribute to the clinical success of diagnostics and drug delivery systems for low-resource settings, including the need to engage key stakeholders at an early stage, and provide recommendations for the clinical translation of future medical technologies.
S1PR1 serves as a viable drug target against pulmonary fibrosis by increasing the integrity of the endothelial barrier of the lung
Authors: Mengyao Hao, Rong Fu, Jun Tai, Zhenhuan Tian, Xia Yuan, Yang Chen, Mingjin Wang, Huimin Jiang, Ming Ji, Fangfang Lai, Nina Xue, Liping Bai, Yizhun Zhu, Xiaoxi Lv, Xiaoguang Chen, Jing Jin
Journal: Acta Pharmaceutica Sinica B (2022)

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with unclear etiology and limited treatment options. The median survival time for IPF patients is approximately 2–3 years and there is no effective intervention to treat IPF other than lung transplantation. As important components of lung tissue, endothelial cells (ECs) are associated with pulmonary diseases. However, the role of endothelial dysfunction in pulmonary fibrosis (PF) is incompletely understood. Sphingosine-1-phosphate receptor 1 (S1PR1) is a G protein-coupled receptor highly expressed in lung ECs. Its expression is markedly reduced in patients with IPF. Herein, we generated an endothelial-conditional S1pr1 knockout mouse model which exhibited inflammation and fibrosis with or without bleomycin (BLM) challenge. Selective activation of S1PR1 with an S1PR1 agonist, IMMH002, exerted a potent therapeutic effect in mice with bleomycin-induced fibrosis by protecting the integrity of the endothelial barrier. These results suggest that S1PR1 might be a promising drug target for IPF therapy.